乙酰甲喹临床前毒理学研究
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摘要
从二十世纪七十年代开始,喹噁啉1,4-氮氧化衍生物被认为是具有广泛生物活性的化学物质。它们被广泛用于促进动物生长和提高饲料转化率。卡巴氧和喹乙醇引起肝毒性,肾上腺毒性,遗传毒性,光敏毒性,生长繁殖毒性以及致癌遗传毒性,已经被禁用或者限制使用在动物饲料中。乙酰甲喹是新一代的喹嗯啉类衍生物,被中国允许使用于家禽和家畜。然而,根据我们的了解,对乙酰甲喹的毒性并没有进行深入的研究。为了研究乙酰甲喹的毒性,进行临床前毒理试验,以便能对乙酰甲喹进行安全评估。
1遗传毒性试验
1.1细菌回复突变试验/Ames实验。用6株鼠伤寒沙门氏菌(TA97,TA98,TA100, TA102, TA1535,和TA1537)以及S9检测乙酰甲喹的基因突变特性。S9用苯巴比妥钠和p-萘黄酮多次诱导大鼠获得。乙酰甲喹剂量为1,2.6,6.9,18.2和50μg/板。TA97和TA 1535测试菌株(不加S9),浓度≥1 pg/ml；TA98,TA100和TA1537浓度≥2.6 pg/ml；TA102,浓度≥6.9μg/ml,不加鼠肝S9,可以观察到明显的基因突变现象。
1.2染色体畸变实验为研究乙酰甲喹的潜在致突变性,对V79细胞进行染色体畸变分析。乙酰甲喹5个不同的浓度(0,1.25,2.5,5和10 pg/ml)。结果显示：加或不加肝S9均可诱导V79染色体畸变。
1.3体内微核试验将昆明小白鼠暴露于乙酰甲喹药物作用下,观察骨髓嗜多然红细胞,检测诱导微核产生的能力。以单一剂量0,5,50和500 mg/kg b.w.分别给予8只雌性小白鼠和8只雄性小白鼠。结果显示：以500 mg/kg b.w的剂量给予的雌雄小鼠出现显著的微核数量。
2急性毒性试验采用OECD指南425规定的Up and Down procedure (UDP)法,用雌雄Wistar大鼠,研究乙酰甲喹的LD50值。乙酰甲喹溶于0.5%的硝酸纤维素钠中,口服给予单一剂量175,550或2000 mg/kg b.w。观察14d,通过AOT425统计方案评估LD50值。结果显示：Wistar大鼠的LD50为550mg/kg b.w.,昆明小白鼠LD50为988.4 mg/kg b.w.。
3临床前90d喂养实验为研究乙酰甲喹的临川前毒性,以0,55,110和275mg/kg的剂量饲喂Wistar大鼠,275 mg/kg的剂量组大鼠出现明显体重下降。90 d后进行尸检,发现给予275 mg/kg剂量的雄性大鼠肾脏重量明显减小,而雌性肝脏和肾上腺增加。雄性大鼠丙氨酸转移酶,丙二醛浓度,雌性大鼠的超氧化物歧化酶,天冬氨酸氨基转移酶增加。275 mg/kg剂量下,还可以观察到雌雄大鼠显著的钠,钾水平下降。我们得出结论,乙酰甲喹能导致肝脏和肾上腺组织学变化,以及血清学上的诸多改变。
4鼠的喂养致畸试验和两代繁殖试验根据目前FDA指南,研究乙酰甲喹的潜在的两代繁殖毒性以及致畸毒性。Wistar大鼠雌雄各25只,浓度剂量为0,25,55,110和275 mg/kg。F0代大鼠给药12周,在交配前,交配,妊娠,哺乳一直到死亡。F1代大鼠断奶后以同样方式给药。F2代维持21d的泌乳期,然后处死。F1代再次交配观察致畸毒性。临床观察,体重和饲料消耗率。乙酰甲喹275 mg/kg的剂量组发现F0和F1代雌性大鼠主要的观察指标体重,卵巢和肾上腺重量明显比对照组降低。275 mg/kg,的剂量组肝,肾上腺和睾丸出现萎缩。致畸毒性试验中胚胎重量下降,乙酰甲喹具有胚胎毒性。
5长期、慢性毒性试验
5.1长期毒性试验研究雄性大鼠肾上腺剂量依赖性长期毒性。大鼠以5个不同的剂量(0,25,55,110和275 mg/kg)饲喂乙酰甲喹180 d。观察到实验组血浆钾离子水平明显比对照组出现明显的剂量依赖性增加。高剂量绍(110,275 mg/kg)发现血浆钠离子水平下降,皮质酮和醛固酮释放减少。而且275mg/kg剂量组的肾上腺出现明显的组织损伤。为更深一步研究乙酰甲喹的肾上腺毒性机理,检测血液中氧化指标和肾上腺中5个重要酶醛固酮和皮质酮基因的mRNA水平。110,275 mg/kg剂量组,谷胱甘肽还原酶和超氧化物歧化酶减少。同样的剂量下,乙酰甲喹下调CYP11A1,CYP11B1和CYP11B2基因的mRNA表达,上调位于内置网上的CYP21和3β-HSD基因表达。结论：乙酰甲喹对雄性大鼠肾上腺造成剂量依赖性长期毒性,因此提示乙酰甲喹对动物和消费者的毒性,机理可能涉及到氧化应激和类固醇合成。
5.2长期睾丸毒性试验该实验设计研究乙酰甲喹通过氧化应激和甾体基因表达引起的睾丸毒性,以及睾丸毒性机理。成年雄性大鼠分别饲喂不同浓度的的乙酰甲喹(0,25,55,110和275 mg/kg),180d。和对照组相比,剂量组110和275 mg/kg的SOD,GSH和(8-OHdG)明显上高,仅275 mg/kg剂量组MDA轻微上升。更近一步研究,用LC/MS-IT-TOF分析,发现代谢物M11。275 mg/kg剂量组体重,睾丸重量,睾酮以及110和275 mg/kg剂量组的血清卵泡刺激激素下降,而LH水平上升。尸检发现生殖细胞耗竭,生精小管以及睾丸收缩管内容物。和对照组相比,275 mg/kg剂量组,睾丸中StAR,P450scc和1713-HSD基因表达水平明显下降,而110 mg/kg剂量组的AR和3β-HSD mRNA表达显著上升。总之,我们第一次发现直接的证据：乙酰甲喹体内通过N→O基团还原代谢,产生自由基。这可能有助于更好的理解喹噁啉类衍生物所引起的雄性不育问题。
Since 1970s, quinoxaline 1,4-dioxide derivatives (QdNOs) have been regarded as an interesting range of biological active compounds. They are widely used in subtherapeutic levels to promote growth and improve efficiency of feed conversion in animal feed. QdNO derivatives, carbadox (CBX) and olaquindox (OLA) had raised serious health hazards of hepatotoxicity, adrenal toxicity, genotoxicity, phototoxicity, developmental and reproductive toxicity and carcinogenicity and been been prohibited or limited to use in animal feed. Mequindox (MEQ) is a novel quinoxaline derivative this family, have been approved in China for use in diet for livestock and poultry. However, according to our knowledge, a comprehensive toxicological evaluation of MEQ has not yet conducted. To investigate the toxicity of MEQ, preclinical toxicity tests were conducted to accumulate information for safety evaluation of this important agent.
1 Genotoxicity tests
1.1 Bacterial Reverse Mutation test/Ames test. The mutagenicity of MEQ was tested in a reverse mutation assay using six S. typhimurium strains (TA97, TA98, TA100, TA102, TA1535, and TA1537) with and without S9-mix from phenobarbital sodium andβ-Naphthoflavone induced rats using triplicate plates. The tests were conducted with doses 1,2.6,6.9,18.2 and 50μg/plate MEQ. A clear mutagenic response was seen in strains TA97 and TA 1535 (without S9) at concentrations≥1μg/ml, TA98, TA100 and TA1537 at concentrations≥2.6μg/ml, and TA102 at concentrations≥6.9μg/ml, with or without rat liver S9-mix.
1.2 Chromosomal aberration test. To investigate the mutagenic potential of MEQ in cell cultures, chromosomal aberration test was conducted in V79 cell line. MEQ was administed to 5 different concentrations (0,1.25,2.5,5 and 10). The results had shown that there was induction of chromosome aberrations in cultured V79 cells with or without S9 at concentrations≥1.25μg/ml.
1.3 In-vivo micronucleus assay. The test was performed to test the induction of micronuclei in polychromatic erythrocytes from femural bone marrow of Kunming mice resulting from exposure to MEQ. The MEQ was administered to groups of eight male and eight female mice at a single dose level of 0,5,50, and 500 mg/kg b.w. The results show that MEQ can cause a significant increase in the number of micronuclei at doses of 50 mg/kg b.w. in both sexes of mice.
2 Acute toxicity test. To determine the LD50 values in female Wistar rats and female Kunming mice, Up and Down procedure (UDP) was performed according to the OECD Guideline 425. MEQ was suspended in 0.5% carboxymethyl-cellulose solution (CMC) and given as a single oral dose of 175, 550 or 2000 mg/kg body weight by gavage. The animals were monitored for up to 14 days and estimated LD50 values were calculated by AOT425 statistical program. The results showed that the LD50 value was 550 mg/kg b.w. in Wistar rats and 988.4 mg/kg b.w. in Kunming mice.
3 subchronic 90-day feeding test in rats. To investigate the potential subchronic toxicity of MEQ, Wistar rats were fed diets containing 0,55,110 or 275 mg MEQ/kg. There was a reduction in body weight of rats fed 275 mg MEQ/kg diet. At 90 days autopsy, a significant decrease in the kidney weight was observed in males while an increase in relative liver and adrenal weights were observed in females fed 275 mg MEQ/kg diet. There was a significant increased in alanine-aminotransferase (ALT) and malondialdehyde (MDA) concentrations in males, superoxide dismutase (SOD) activities in females, and aspartate-aminotransferase (AST) levels in serum of both genders fed 275 mg MEQ/kg diet. Other toxic effects of 275 mg MEQ/kg diet included significant decrease in sodium and significant increase in potassium concentrations in serum in both genders. We may conclude that MEQ can induce hepatic and adrenal histological changes as well as leaking of different serum constituents in Wistar rats. Based on the subchronic study,110 mg/kg diet was determined to be NOAEL in both sexes of Wistar rats.
4 Feeding teratogenic and two generation reproduction test in rats. The potential two generation reproductive toxicity and teratogenic studies for MEQ were conducted using current FDA guidelines. Groups of 25 male and 25 female Wistar rats were offered dietary concentrations of 0,25,55,110 and 275 mg/kg MEQ. Parental (F0) generation rats (4-6 weeks old) were treated for 12 weeks prior to mating, throughout mating, gestation and lactation until sacrificed. F1-generation rats were dosed similarly, beginning at weaning. The F2a generation pups were maintained through 21 days of lactation and then sacrificed. The F1-generation rats were mated again to observe teratogenicity. Clinical observations, body weights and feed consumption were recorded routinely. The mean body weight, ovary and adrenal weights in the females of F0 and F1 given 275 mg/kg MEQ were significantly suppressed than the controls. At 275 mg/kg, liver, kidneys adrenal and testis have degenerative changes. Early pup mortality was found in the high dose groups. In the teratogenic test, there was decrease in the weight of pups with kinky tail. The MEQ was found to be embryotoxic at 275 mg/kg. Based on this study,25 mg/kg diet was determined to be NOAEL in the Wistar rats.
5. Long term/chronic toxicity test in rats.
5.1 Long term adrenal toxicity. This study was to investigate the dose-dependent long-term toxicity in the adrenal of male rats. Rats were fed with MEQ for 180 days at five different doses (0,25,55,110 and 275 mg/kg, respectively). An increase in plasma potassium (K+) levels was observed in MEQ groups in comparison to control animals, and this increase was dose-dependent. Both high doses (110,275 mg/kg) of MEQ treatment showed a significant decline in plasma sodium (Na+), corticosterone and aldosterone release. Moreover, the 275 mg/kg treated group exhibited a marked pathological damage in adrenal tissue. To further explore the mechanism of MEQ on adrenal toxicity, oxidative indexes in blood and mRNA levels of five enzymes that are important for aldosterone and corticosterone biosynthesis were detected. Significant changes of reduced glutathione (GSH) and superoxide dismutase (SOD) in plasma were observed in the group treated at high doses (110,275 mg/kg). At the same doses, MEQ treatment down- regulated the mRNA levels of CYP11A1, CYP11B1 and CYP11B2 which located in mitochondria, but up-regulated mRNA levels of CYP21 and 3β-HSD which located in endoplasmic reticulum. In conclusion, we reported the dose-dependent long-term toxicity of MEQ on adrenal gland in male rats, which raise awareness of its toxic effects to animals and consumers, and its mechanism may involve in oxidative stress and steroid hormone biosynthesis pathway.
5.2 Long term testicular toxicity. This study was designed to investigate the hypothesis that MEQ exerts testicular toxicity by causing oxidative stress and steroidal gene expression profiles and determine mechanism of MEQ testicular toxicity. In this study, adult male Wistar rats were fed with MEQ for 180 days at five different doses as 0,25,55,110 and 275 mg/kg, respectively. In comparison to control, SOD, GSH and 8-hydroxydeoxyguanosine (8-OHdG) levels were elevated at 110 and 275 mg/kg MEQ, whereas the MDA level was slightly increase at only 275 mg/kg. Furthermore, in LC/MS-IT-TOF analysis, one metabolite 2-isoethanol 4-desoxymequindox (M11) was found in the testis. There was significant decrease in body weight, testicular weight and testosterone at 275 mg/kg, serum follicular stimulating hormone (FSH) at 110 and 275 mg/kg, while lutinizing hormone (LH) levels were elevated at 110 mg/kg. Moreover, histopathology of testis exhibited germ cell depletion, contraction of seminiferous tubules and disorganization of the tubular contents of testis. Compared with control, mRNA expression of StAR, P450scc and 17β-HSD in testis was significantly decreased after exposure of 275 mg/kg MEQ while AR and 3P-HSD mRNA expression were significantly elevated at the 110 mg/kg MEQ group. Taken together, our findings provide the first and direct evidence in vivo for the formation of free radicals during the MEQ metabolism through N→O group reduction, which may have implications to understand the possible mechanism of male infertility related to quinoxaline derivatives.
1遗传毒性试验
1.1细菌回复突变试验/Ames实验。用6株鼠伤寒沙门氏菌(TA97,TA98,TA100, TA102, TA1535,和TA1537)以及S9检测乙酰甲喹的基因突变特性。S9用苯巴比妥钠和p-萘黄酮多次诱导大鼠获得。乙酰甲喹剂量为1,2.6,6.9,18.2和50μg/板。TA97和TA 1535测试菌株(不加S9),浓度≥1 pg/ml；TA98,TA100和TA1537浓度≥2.6 pg/ml；TA102,浓度≥6.9μg/ml,不加鼠肝S9,可以观察到明显的基因突变现象。
1.2染色体畸变实验为研究乙酰甲喹的潜在致突变性,对V79细胞进行染色体畸变分析。乙酰甲喹5个不同的浓度(0,1.25,2.5,5和10 pg/ml)。结果显示：加或不加肝S9均可诱导V79染色体畸变。
1.3体内微核试验将昆明小白鼠暴露于乙酰甲喹药物作用下,观察骨髓嗜多然红细胞,检测诱导微核产生的能力。以单一剂量0,5,50和500 mg/kg b.w.分别给予8只雌性小白鼠和8只雄性小白鼠。结果显示：以500 mg/kg b.w的剂量给予的雌雄小鼠出现显著的微核数量。
2急性毒性试验采用OECD指南425规定的Up and Down procedure (UDP)法,用雌雄Wistar大鼠,研究乙酰甲喹的LD50值。乙酰甲喹溶于0.5%的硝酸纤维素钠中,口服给予单一剂量175,550或2000 mg/kg b.w。观察14d,通过AOT425统计方案评估LD50值。结果显示：Wistar大鼠的LD50为550mg/kg b.w.,昆明小白鼠LD50为988.4 mg/kg b.w.。
3临床前90d喂养实验为研究乙酰甲喹的临川前毒性,以0,55,110和275mg/kg的剂量饲喂Wistar大鼠,275 mg/kg的剂量组大鼠出现明显体重下降。90 d后进行尸检,发现给予275 mg/kg剂量的雄性大鼠肾脏重量明显减小,而雌性肝脏和肾上腺增加。雄性大鼠丙氨酸转移酶,丙二醛浓度,雌性大鼠的超氧化物歧化酶,天冬氨酸氨基转移酶增加。275 mg/kg剂量下,还可以观察到雌雄大鼠显著的钠,钾水平下降。我们得出结论,乙酰甲喹能导致肝脏和肾上腺组织学变化,以及血清学上的诸多改变。
4鼠的喂养致畸试验和两代繁殖试验根据目前FDA指南,研究乙酰甲喹的潜在的两代繁殖毒性以及致畸毒性。Wistar大鼠雌雄各25只,浓度剂量为0,25,55,110和275 mg/kg。F0代大鼠给药12周,在交配前,交配,妊娠,哺乳一直到死亡。F1代大鼠断奶后以同样方式给药。F2代维持21d的泌乳期,然后处死。F1代再次交配观察致畸毒性。临床观察,体重和饲料消耗率。乙酰甲喹275 mg/kg的剂量组发现F0和F1代雌性大鼠主要的观察指标体重,卵巢和肾上腺重量明显比对照组降低。275 mg/kg,的剂量组肝,肾上腺和睾丸出现萎缩。致畸毒性试验中胚胎重量下降,乙酰甲喹具有胚胎毒性。
5长期、慢性毒性试验
5.1长期毒性试验研究雄性大鼠肾上腺剂量依赖性长期毒性。大鼠以5个不同的剂量(0,25,55,110和275 mg/kg)饲喂乙酰甲喹180 d。观察到实验组血浆钾离子水平明显比对照组出现明显的剂量依赖性增加。高剂量绍(110,275 mg/kg)发现血浆钠离子水平下降,皮质酮和醛固酮释放减少。而且275mg/kg剂量组的肾上腺出现明显的组织损伤。为更深一步研究乙酰甲喹的肾上腺毒性机理,检测血液中氧化指标和肾上腺中5个重要酶醛固酮和皮质酮基因的mRNA水平。110,275 mg/kg剂量组,谷胱甘肽还原酶和超氧化物歧化酶减少。同样的剂量下,乙酰甲喹下调CYP11A1,CYP11B1和CYP11B2基因的mRNA表达,上调位于内置网上的CYP21和3β-HSD基因表达。结论：乙酰甲喹对雄性大鼠肾上腺造成剂量依赖性长期毒性,因此提示乙酰甲喹对动物和消费者的毒性,机理可能涉及到氧化应激和类固醇合成。
5.2长期睾丸毒性试验该实验设计研究乙酰甲喹通过氧化应激和甾体基因表达引起的睾丸毒性,以及睾丸毒性机理。成年雄性大鼠分别饲喂不同浓度的的乙酰甲喹(0,25,55,110和275 mg/kg),180d。和对照组相比,剂量组110和275 mg/kg的SOD,GSH和(8-OHdG)明显上高,仅275 mg/kg剂量组MDA轻微上升。更近一步研究,用LC/MS-IT-TOF分析,发现代谢物M11。275 mg/kg剂量组体重,睾丸重量,睾酮以及110和275 mg/kg剂量组的血清卵泡刺激激素下降,而LH水平上升。尸检发现生殖细胞耗竭,生精小管以及睾丸收缩管内容物。和对照组相比,275 mg/kg剂量组,睾丸中StAR,P450scc和1713-HSD基因表达水平明显下降,而110 mg/kg剂量组的AR和3β-HSD mRNA表达显著上升。总之,我们第一次发现直接的证据：乙酰甲喹体内通过N→O基团还原代谢,产生自由基。这可能有助于更好的理解喹噁啉类衍生物所引起的雄性不育问题。
Since 1970s, quinoxaline 1,4-dioxide derivatives (QdNOs) have been regarded as an interesting range of biological active compounds. They are widely used in subtherapeutic levels to promote growth and improve efficiency of feed conversion in animal feed. QdNO derivatives, carbadox (CBX) and olaquindox (OLA) had raised serious health hazards of hepatotoxicity, adrenal toxicity, genotoxicity, phototoxicity, developmental and reproductive toxicity and carcinogenicity and been been prohibited or limited to use in animal feed. Mequindox (MEQ) is a novel quinoxaline derivative this family, have been approved in China for use in diet for livestock and poultry. However, according to our knowledge, a comprehensive toxicological evaluation of MEQ has not yet conducted. To investigate the toxicity of MEQ, preclinical toxicity tests were conducted to accumulate information for safety evaluation of this important agent.
1 Genotoxicity tests
1.1 Bacterial Reverse Mutation test/Ames test. The mutagenicity of MEQ was tested in a reverse mutation assay using six S. typhimurium strains (TA97, TA98, TA100, TA102, TA1535, and TA1537) with and without S9-mix from phenobarbital sodium andβ-Naphthoflavone induced rats using triplicate plates. The tests were conducted with doses 1,2.6,6.9,18.2 and 50μg/plate MEQ. A clear mutagenic response was seen in strains TA97 and TA 1535 (without S9) at concentrations≥1μg/ml, TA98, TA100 and TA1537 at concentrations≥2.6μg/ml, and TA102 at concentrations≥6.9μg/ml, with or without rat liver S9-mix.
1.2 Chromosomal aberration test. To investigate the mutagenic potential of MEQ in cell cultures, chromosomal aberration test was conducted in V79 cell line. MEQ was administed to 5 different concentrations (0,1.25,2.5,5 and 10). The results had shown that there was induction of chromosome aberrations in cultured V79 cells with or without S9 at concentrations≥1.25μg/ml.
1.3 In-vivo micronucleus assay. The test was performed to test the induction of micronuclei in polychromatic erythrocytes from femural bone marrow of Kunming mice resulting from exposure to MEQ. The MEQ was administered to groups of eight male and eight female mice at a single dose level of 0,5,50, and 500 mg/kg b.w. The results show that MEQ can cause a significant increase in the number of micronuclei at doses of 50 mg/kg b.w. in both sexes of mice.
2 Acute toxicity test. To determine the LD50 values in female Wistar rats and female Kunming mice, Up and Down procedure (UDP) was performed according to the OECD Guideline 425. MEQ was suspended in 0.5% carboxymethyl-cellulose solution (CMC) and given as a single oral dose of 175, 550 or 2000 mg/kg body weight by gavage. The animals were monitored for up to 14 days and estimated LD50 values were calculated by AOT425 statistical program. The results showed that the LD50 value was 550 mg/kg b.w. in Wistar rats and 988.4 mg/kg b.w. in Kunming mice.
3 subchronic 90-day feeding test in rats. To investigate the potential subchronic toxicity of MEQ, Wistar rats were fed diets containing 0,55,110 or 275 mg MEQ/kg. There was a reduction in body weight of rats fed 275 mg MEQ/kg diet. At 90 days autopsy, a significant decrease in the kidney weight was observed in males while an increase in relative liver and adrenal weights were observed in females fed 275 mg MEQ/kg diet. There was a significant increased in alanine-aminotransferase (ALT) and malondialdehyde (MDA) concentrations in males, superoxide dismutase (SOD) activities in females, and aspartate-aminotransferase (AST) levels in serum of both genders fed 275 mg MEQ/kg diet. Other toxic effects of 275 mg MEQ/kg diet included significant decrease in sodium and significant increase in potassium concentrations in serum in both genders. We may conclude that MEQ can induce hepatic and adrenal histological changes as well as leaking of different serum constituents in Wistar rats. Based on the subchronic study,110 mg/kg diet was determined to be NOAEL in both sexes of Wistar rats.
4 Feeding teratogenic and two generation reproduction test in rats. The potential two generation reproductive toxicity and teratogenic studies for MEQ were conducted using current FDA guidelines. Groups of 25 male and 25 female Wistar rats were offered dietary concentrations of 0,25,55,110 and 275 mg/kg MEQ. Parental (F0) generation rats (4-6 weeks old) were treated for 12 weeks prior to mating, throughout mating, gestation and lactation until sacrificed. F1-generation rats were dosed similarly, beginning at weaning. The F2a generation pups were maintained through 21 days of lactation and then sacrificed. The F1-generation rats were mated again to observe teratogenicity. Clinical observations, body weights and feed consumption were recorded routinely. The mean body weight, ovary and adrenal weights in the females of F0 and F1 given 275 mg/kg MEQ were significantly suppressed than the controls. At 275 mg/kg, liver, kidneys adrenal and testis have degenerative changes. Early pup mortality was found in the high dose groups. In the teratogenic test, there was decrease in the weight of pups with kinky tail. The MEQ was found to be embryotoxic at 275 mg/kg. Based on this study,25 mg/kg diet was determined to be NOAEL in the Wistar rats.
5. Long term/chronic toxicity test in rats.
5.1 Long term adrenal toxicity. This study was to investigate the dose-dependent long-term toxicity in the adrenal of male rats. Rats were fed with MEQ for 180 days at five different doses (0,25,55,110 and 275 mg/kg, respectively). An increase in plasma potassium (K+) levels was observed in MEQ groups in comparison to control animals, and this increase was dose-dependent. Both high doses (110,275 mg/kg) of MEQ treatment showed a significant decline in plasma sodium (Na+), corticosterone and aldosterone release. Moreover, the 275 mg/kg treated group exhibited a marked pathological damage in adrenal tissue. To further explore the mechanism of MEQ on adrenal toxicity, oxidative indexes in blood and mRNA levels of five enzymes that are important for aldosterone and corticosterone biosynthesis were detected. Significant changes of reduced glutathione (GSH) and superoxide dismutase (SOD) in plasma were observed in the group treated at high doses (110,275 mg/kg). At the same doses, MEQ treatment down- regulated the mRNA levels of CYP11A1, CYP11B1 and CYP11B2 which located in mitochondria, but up-regulated mRNA levels of CYP21 and 3β-HSD which located in endoplasmic reticulum. In conclusion, we reported the dose-dependent long-term toxicity of MEQ on adrenal gland in male rats, which raise awareness of its toxic effects to animals and consumers, and its mechanism may involve in oxidative stress and steroid hormone biosynthesis pathway.
5.2 Long term testicular toxicity. This study was designed to investigate the hypothesis that MEQ exerts testicular toxicity by causing oxidative stress and steroidal gene expression profiles and determine mechanism of MEQ testicular toxicity. In this study, adult male Wistar rats were fed with MEQ for 180 days at five different doses as 0,25,55,110 and 275 mg/kg, respectively. In comparison to control, SOD, GSH and 8-hydroxydeoxyguanosine (8-OHdG) levels were elevated at 110 and 275 mg/kg MEQ, whereas the MDA level was slightly increase at only 275 mg/kg. Furthermore, in LC/MS-IT-TOF analysis, one metabolite 2-isoethanol 4-desoxymequindox (M11) was found in the testis. There was significant decrease in body weight, testicular weight and testosterone at 275 mg/kg, serum follicular stimulating hormone (FSH) at 110 and 275 mg/kg, while lutinizing hormone (LH) levels were elevated at 110 mg/kg. Moreover, histopathology of testis exhibited germ cell depletion, contraction of seminiferous tubules and disorganization of the tubular contents of testis. Compared with control, mRNA expression of StAR, P450scc and 17β-HSD in testis was significantly decreased after exposure of 275 mg/kg MEQ while AR and 3P-HSD mRNA expression were significantly elevated at the 110 mg/kg MEQ group. Taken together, our findings provide the first and direct evidence in vivo for the formation of free radicals during the MEQ metabolism through N→O group reduction, which may have implications to understand the possible mechanism of male infertility related to quinoxaline derivatives.
引文
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